Triggering cryptic natural product biosynthesis in microorganisms

Abstract

Natural products from microorganisms are a crucial source for novel therapeutics. Even so, it seems that many valuable compounds are overlooked when culturing microbes under standardized laboratory conditions. Many biosynthesis genes remain silent and such "cryptic" or "orphan" pathways are only activated under specific conditions. This report gives an overview on the strategies to trigger biosynthetic pathways to yield "cryptic natural products" through external cues, co-cultivation and genomic approaches such as genome-mining, epigenetic remodeling, and engineered pathway activation.

Fradiamine A, a new siderophore from the deep-sea actinomycete Streptomyces fradiae MM456M-mF7

“…These factors all affect the expression of secondary metabolite genes. 5,6 Numerous novel bioactive compounds were isolated from marine organisms. 7 Marine actinomycetes also produced novel useful compounds, including the anticancer candidates salinosporamide A isolated from Salinispora tropica 8 and thiocoraline isolated from Micromonospora marina.…”

Aspernidine A and B, prenylated isoindolinone alkaloids from the model fungus Aspergillus nidulans

“…Several gene loci encoding diverse metabolic pathways seem to lack expression in the absence of particular physical or chemical stimuli. 4 Mining the genome of Aspergillus nidulans for putative biosynthesis gene clusters revealed biosynthetic abilities for the production of up to 28 polyketides and 24 nonribosomally synthesized peptides. 5,6 However, this abundance of gene clusters clearly outnumbers the known secondary metabolites of this fungus.…”

“…Since the early days of fermentations, it is known that the choice of the cultivation parameters is critical to the number and type of secondary metabolites produced by microorganisms. 4 Thus, the formation of cryptic natural products can up to a certain extent be triggered by a systematic variation of standard fermentation parameters to increase the number of secondary compounds produced in the bacterial or fungal culture. 15,16 On the basis of the assumption that changing environmental conditions can shift the metabolic profile of an organism, we systematically varied the cultivation parameters to reinvestigate the metabolome of A. nidulans.…”

“…To gain access to this untapped reservoir of potentially bioactive natural products, various strategies to induce the expression of silent genes have been developed. 4,7 Important recent examples involve the ectopic expression of a regulatory gene, 8 the induction of a transcription activator by promotor exchange, 9 as well as modulation of the epigenetic regulation of biosynthetic genes at the chromatin level. [10][11][12][13] Furthermore, it was shown that the intimate contact between A. nidulans and a soil-dwelling actinomycete may lead to the specific induction of a cryptic polyketide gene cluster.…”

“…From an upscaled culture (14 l), the compounds were isolated and their structures elucidated by one-and two-dimensional NMR and MS measurements. For compound 1, a molecular formula of C 24 H 33 NO 4 was established by HRESI-MS analysis. The 13 C NMR spectrum displayed 24 C-atoms, which were assigned to four methyl, one methoxy, six methylene, four sp 2 -hybridized and nine quaternary carbons by DEPT measurements.…”